The therapeutic utility of wild type or recombinantly modified viruses are well known in the art. Early reports on the therapeutic use of viruses date from the 1950""s. For example, in 1952, Southam and Moore reported on the use of Vaccinia, Newcastle Disease, West Nile, Ilheus and Bunyamwera, and Egypt 101 viruses for the treatment of a variety of cancers. Cancer 5:1025-1034 (1952). In 1956, Newman and Moore summarized the results of the treatment of fifty-seven cancer patients with a variety of viruses. Cancer 7:106-118. In 1956, Smith, et al. reported on the therapeutic use of adenovirus for the treatment of cervical cancer. Cancer 9: 1211-1218. Southam presented a summary of the clinical experience obtained at the Sloan-Kettering Institute on the efficacy of viruses as anti-neoplastic agents in 1960. Transactions of the New York Academy of Sciences 22:657-673. More recent reports demonstrate a continuing interest in the therapeutic use of viruses. Taylor, et al. presented results suggesting the therapeutic use of bovine enterovirus-1 for the treatment of solid and ascites tumors based on experiments conducted in mice. PNAS (USA) 68:836-840 (1971). Additional human clinical trials continued to demonstrate promise in this field as illustrated by the use of Mumps virus to treat a variety of cancers. Asada, T. (1974) Cancer 34:1907-1928.
An increased understanding the viral genome and the advent of recombinant DNA techniques permitted the manipulation of viruses to possess particular desirable features. For example, a recombinant adenovirus containing a modification to the E1B-55K region is currently in Phase II clinical trials in human beings. Additionally, recombinant viral vectors have been employed for the delivery of a variety of therapeutic substances. Most notably, recombinant adenoviral vectors have been employed in anti-cancer therapies where the viral genome has been modified to encode a tumor suppressor gene. In particular, a replication deficient virus expressing the p53 tumor suppressor gene has successfully completed Phase I and is currently in Phase II/III clinical development.
However, the clinical experience with such vectors has demonstrated that a significant fraction of the therapeutic virus which is administered to a patient is disabled by the presence of neutralizing antibodies in the serum and reticular endothelial system (RES). This obstacle is particularly acute when an adenovirus is used as the vehicle for delivery of a transgene since a act significant portion of the human population has naturally been exposed to adenoviruses vectors and possesses pre-existing immunity. Consequently, the administration of a significant excess of the recombinant adenoviral vector is administered to the patient to xe2x80x9cdose throughxe2x80x9d the pre-existing immune response. Additionally, even if no pre-existing immune response was present, following administration of a therapeutic virus the mammal will generally produce an immune response to the virus. This xe2x80x9cinducedxe2x80x9d antiviral immune response complicates additional courses of therapy with the therapeutic virus in a manner similar to the pre-existing immune response induced by exposure to the virus in the environment. This is not desirable from a clinical standpoint in that it may present complications to the already ill patient. Furthermore, from a commercial standpoint a large quantity of material is wasted in an attempt to dose through the preexisting immune response. Consequently, there is a need in the art to reduce the pre-existing immune response to therapeutic viral vectors.
A variety of methods have been employed in an attempt to cope with this problem. In one method, the virus is coated with masking agents such as polyethylene glycol (so called xe2x80x9cPEGylationxe2x80x9d) to coat the virus and mask the immunological determinants of the virus. This is a cumbersome process requiring that the virus be coated with an agent and the long-term stability of the PEGylated virus has yet to be demonstrated as commercially feasible. Other avenues include co-administration of immunosuppressive agents. However, the administration of broad spectrum immunosuppressive agents is not desirable. In particular, there is mounting evidence to suggest that a significant complement to anti-cancer therapy is that the immune response augments the anti-tumor activity of the therapeutic virus. This phenomenon has been observed for some time and many individuals have suggested that amplification of the immune response to tumor antigens may be of therapeutic benefit. Consequently, it is not generally desirable to broadly suppress the immune system of a cancer patient.
Consequently there remains a need in the art to reduce the pre-existing humoral immune response to a therapeutic viral vector. The present invention addresses this need.
The present invention provides compositions, devices and methods to remove antiviral antibodies from the blood of mammals. The compositions and methods of the present invention may be practiced in conjunction with administration of a therapeutic virus. The invention further provides an immunoaffinity material comprising a chromatographic support material derivatized with antigenic determinants of viral coat. The invention further provides an improved apheresis apparatus to remove antiviral antibodies from the blood and, in particular from plasma. The present invention further provides therapeutic methods involving the use of such apparatus.